The voltage-gated sodium channel Nav1.6 is expressed in both the CNS and PNS, the initial segment, and nodes of Ranvier of adult myelinated axons (Burgess et al., 1995; Schaller et al., 1995; Boiko et al., 2001; Black et al., 2002). Nav1.6 is distinct from the other sodium channels in that it expresses resurgent and persistent currents (Raman and Bean, 1997; Smith et al., 1998), both of which have been shown to be cell-type dependent, suggesting a cell-specific modulator (Grieco et al., 2002). Determination and characterization of the interaction of proteins with Nav1.6 is crucial in order to ascertain the mechanisms behind the biophysical modulation, and the distribution and clustering of this channel. A yeast two-hybrid screen using the C-terminus of Nav1.6 found that a member of the fibroblast growth factor family, FHF2b (FGF13b), interacts with Nav1.6. In this study, the interaction between Nav1.6 and FHF2b will be characterized in mammalian cells. In the second aim, the modulatory effects of this interaction on the biophysical properties of the channel and channel localization will be determined. The third aim will determine if the Nav1.6/FHF2b complex recruits a kinase, and if the biophysical properties of the channel are modulated by kinase interactions or activation. Finally, this proposal will look at the effect of calmodulin, another C-terminal binding protein, on the interaction between Nav1.6 and FHF2b. These studies on the modulation of Nav1.6 may have clinical application due to the involvement of this channel in neurological disorders.